The present invention relates to a process for the preparation of radiolabeled meta-halobenzylguanidine, as well as intermediate compounds used in this process.
Radiohalogenated meta-iodobenzylguanidine is an agent useful for imaging the adrenal medulla and its associated neoplasms. Specifically, the compound .sup.131 I-meta-iodobenzylguanidine (.sup.131 I-MIBG) is currently being used for the diagnosis and localization of primary and metastatic pheochromocytomas, neuroblastomas, medullary thyroid carcinomas, paragangliomas, carcinoid ramors and apudomas. .sup.131 I-MIBG is also being evaluated in the therapy of neuroendocrine malignancies, such as carcinoid tumors, pheochromocytomas, and neuroblastomas.
Currently, .sup.131 I-MIBG is prepared by an isotopic exchange method using meta-iodobenzylguanidine (MIBG) and a source of radioiodide. Because isotopic exchange is an equilibrium process the product obtained thereby necessarily contains a significant amount of the carder MIBG and results in product preparations having specific activities generally in the order of 100 Ci/mmol. The administration of a typical 5 mCi dose of .sup.131 I-MIBG made by the isotopic exchange process would result in the co-administration of about 5 mg of MIBG. This amount of MIBG received by the patient may cause unwanted pharmacological effects and is a particular concern in children because of their smaller body weight. Thus, no-carder-added synthesis of .sup.131 I-MIBG would be desirable to circumvent potential problems that may be associated with carder presence.
Vaidyanathan and Zalutsky (Appl. Radiat. Isot., 44(3):621-628, 1993) attempted unsuccessfully to synthesize 3-(tri-n-butylstannyl)benzylquanidine, a compound that would have allowed the introduction of the radioiodine label by iododestannylation as the last step in the synthesis of .sup.131 I-MIBG. Instead, .sub.131 I3-iodobenzylamine was prepared and then converted to .sup.131 I-MIBG with cyanamide; this process has the disadvantage that radioiodine is introduced in the penultimate step of the synthesis rather than in the last step. Vaidyanathan and Zalutsky also reported the synthesis of .sup.131 I-MIBG by iododesilylation of 3-trimethylsilylbenzylguanidine; however, the synthesis of 3-trimethylsilylbenzylguanidine requires multiple steps and is therefore not suitable for large scale production of .sup.131 I-MBG. Thus, there still exists the need for an efficient and practical non-carder-added synthesis of .sup.131 I-MIBG.